The present invention relates to a novel method for the synthesis of piperazine and its derivatives of formula 1, 
wherein R is selected from hydrogen or a lower alkyl group having 1 to 6 carbon atoms or a phenylalkyl group the alkyl of which has 1 to 4 carbon atoms;
R1 is selected from hydrogen, a methyl group, a phenyl group optionally substituted with alkyl having 1 to 6 carbon atoms, a phenylalkyl group the alkyl of which has 1 to 4 carbon atoms; and
R2 is selected from hydrogen, a methyl group, or a fluoromethyl group.
The compounds of formula 1 of the present invention are useful starting materials for the manufacture of a number of pharmaceutically active compounds such as mirtazepine, sparfloxacin, cetirizine, cinnarizine, oxatomide, clozapine and olanzapine.
Piperazine is generally prepared by treating ammonia with ethylenediamine (SU467073), aminoethylethylenediamine (SU427936), monoethanolamine (CN1106000) or diethanolamine (JP58035179); or hydrogenation of N-(aminoethyl)ethanolamine (JP49010513). However, all these processes require high temperature and pressure, and give mixtures making isolation of piperazine difficult.
C. B. Pollard et al in J. Med. Chem. 9, 181-185 (1966) report the preparation of 2-phenylpiperazine starting from xcex1-halophenyl acetic acid ester and ethylenediamine which resulted in the formation of 2-keto-3-phenylpiperazine of formula 2. Further, reduction of the compound of formula 2 with lithium aluminum hydride provides 2-phenylpiperazine of formula 3. The drawback of this method is that the reaction between xcex1-halophenyl acetic acid ester and ethylenediamine gives a polymeric mixture which poses difficulty in isolating the pure compound of formula 2. 
WO 98/08826 teaches the preparation of 2-arylpiperazines from 2-halopyrazine by reaction with an aryl Grignard reagent followed by reduction by hydrogenation in the presence of palladium acetate. The Grignard reaction is not facile as it yields 39% product and further requires the use of expensive catalyst, viz., [1,2 bis (diphenylphosphino) ethane] nickel (II) chloride in high quantity.
U.S. Pat. No. 4,912,110 discloses a process for the preparation of a compound of formula 4. 
wherein:
R3 is H or a C1 to C2 alkyl group,
R4 is H or a C1 to C4 alkyl group,
R5 is H or a C1 to C4 alkyl group and
X is H, F, Cl or Br,
at least one of the symbols R3, R4, R5 and X being different from H.
The process of preparation recommended in U.S. Pat. No. 4,912,110 consists in
A. reacting a 1-phenylalkane-1,2-dione of the formula 5 with ethylenediamine to give 2-phenyldihydropyrazine of the formula 6 wherein X and R3 are as defined above; 
B. subjecting the resulting compound of the formula 6 (where R3 and X=H) to a reduction reaction with a reducing agent, selected especially from the group consisting of, LiAlH4 and NaBH4, to give 2-phenylpiperazine of the formula 3; and
C. if necessary, subjecting the resulting compound of the formula 3 to an alkylation reaction in order to introduce the group R3=C1 to C2 alkyl or the groups R4 and R5 in formula 4 each representing a C1 to C4 alkyl group.
However, the yields of this process are very low. Typically, an overall yield of 6% is obtained for 1-isopropyl-2-methyl-3-phenylpiperazine starting from 1-phenylpropane-1,2-dione.
This patent also suggests that reaction of 1-phenylalkane-1,2-dione of the formula 5 with a monoalkyl ethylenediamine of the formula 7 wherein R and R2 are as defined above, gives phenylpiperazine compounds of formula 8a instead of compounds of the present invention having formula 8b. 
Further, the patent also discloses that N-alkylation of piperazine is carried out in the presence of an alkyl halide and when the alkyl halide is an alkyl iodide, like ICH3, 8b (R=CH3) instead of 8a (R=CH3) is the favored product.
WO 98/08826 describes the reaction of 2-phenylpiperazine 3 with 3,5-bis(trifluoromethylbenzylbromide) to furnish the corresponding 1-alkyl-3-phenylpiperazine. The drawback of this process is that it is carried out at a very low temperature of xe2x88x9278xc2x0 C.
U.S. Pat. No. 4,772,705 discloses the preparation of 1-methyl-3-phenylpiperazine from 2-phenylpiperazine, using methyl iodide as the methylating agent. However, the yield is low (54%) and the reaction requires low temperature conditions (0xc2x0 C.) for selective alkylation at the 1-position.
Also, when the alkylation is performed with methyl iodide on 2-phenylpiperazine 3 (as described by V. M. Dixit et al in Indian Journal Of Chemistry Vol.14B, November 1976, pp 874-878), a mixture of products is obtained, viz., the desired 1-methyl-3-phenylpiperazine 1 (where R=CH3, R1=Ph and R2=H), unreacted 2-phenylpiperazine 3,1-methyl-2-phenylpiperazine 9, and 1,4-dimethyl-2-phenylpiperazine 10. 
N-methylpiperazine can be prepared by reacting formaldehyde with aminoethylethanolamine in the presence of hydrogen over a metallic hydrogenation-dehydrogenation catalyst, as disclosed in U.S. Pat. No. 5,414,087. The method taught in this patent requires use of an expensive catalyst like nickel-copper-chrome.
All of the foregoing patents and publications are incorporated herein by reference.
The principal object of the present invention is to provide a simple and efficient process for preparation of piperazine and its derivatives of the aforesaid formula 1.
A further object of the present invention is to provide a simple and efficient process for the preparation of 1-alkyl-3-phenylpiperazine without the need for alkylation of 2-phenylpiperazine and subsequent formation of 1-alkyl-2-phenylpiperazine and 1,4-dialkyl-2-phenylpiperazine as side products.
Thus the present invention is for a method for the preparation of piperazine and its derivatives of formula 1, 
wherein R is selected from hydrogen, or a lower alkyl group having 1 to 6 carbon atoms or a phenylalkyl group the alkyl of which has 1 to 4 carbon atoms;
R1 is selected from hydrogen, a methyl group, a phenyl group optionally substituted with alkyl having 1 to 6 carbon atoms, a phenylalkyl group the alkyl of which has 1 to 4 carbon atoms; and
R2 is selected from hydrogen, a methyl group, or a fluoromethyl group and wherein the method comprises the steps:
a. reacting an ester of formula 11 with substituted or unsubstituted ethylenediamine 7 to give 3,4-dehydropiperazine-2-one and its derivatives of formula 12
xe2x80x83wherein R, R1, R2 are as defined above and
R6 is a C1 to C4 linear or branched alkyl group; and
b. reacting the 3,4-dehydropiperazine-2-one and its derivatives of formula 12 thus obtained with a reducing agent to yield piperazine and its derivatives of formula 1.
In a preferred embodiment of the present invention, the piperazine derivative of formula 1 is l-methyl-3-phenylpiperazine.
(A) Step (a): Preparation of Compounds of Formula 12
The process of the present invention uses a novel methodology the first step comprising reacting an ester of formula 11 with substituted or unsubstituted ethylenediamine 7 to give 3,4-dehydropiperazine-2-one and its derivatives of formula 12, where R, R1, R2 and R6 are as defined above. 
The starting material of formula 7 is ethylenediamine when R and R2 are both hydrogen. The starting material of formula 7, when R and R2 are as defined above, may be prepared by reacting alkyl or phenylalkyl amine with 2-chloroethyl amine hydrochloride or its derivatives followed by neutralization with an alkali.
According to the process of the present invention step (a) is carried out in the presence of an organic acid, a cation exchange resin, or a mineral acid. The organic acid that is preferably employed is an alkyl, an aryl sulphonic acid, or a C1 to C16 carboxylic acid. The organic acid is preferably acetic acid.
Examples of cation exchange resins which may be used in step (a) of the process of the present invention are polystyrene-sulfonate resins like Ionac C-250H (available from Sybron Chemicals Inc.), Amberlite IR-120H or IR-122H (available from Rohm and Haas), Resintech CG10-H (available from Resintech) or Dow HCES-H or HGR-H (available from Dow Chemicals).
The mineral acid used in step (a) is preferably selected from the group consisting of hydrochloric acid, sulphuric acid, phosphoric acid, perchloric acid or nitric acid.
In step (a), preferably from 0.1 to 10.0 moles of acid are added for 1 mole of substituted or unsubstituted ethylenediamine. More preferably, 0.5 to 2.0 moles of acid are added for 1 mole of substituted or unsubstituted ethylenediamine. Most preferably however, 1 mole of acid is added for 1 mole of substituted or unsubstituted ethylenediamine.
The reaction between the monoalkyl ethylenediamine of formula 7 and the ester of formula 11 is preferably carried out in an inert solvent in which the reactants are soluble. Examples of the solvents that can be employed are C1 to C6 alcohols, such as ethanol or i- or n-propanol, or hydrocarbons, such as toluene, xylene, benzene, or methylene chloride. The most preferred solvents are alkanols and aromatic hydrocarbons with a boiling range between 60 to 120xc2x0 C.
Preferably, the reaction is carried out at reaction temperatures of between about 60 and 120xc2x0 C. The esters of formula 11 employed in the above reaction include those wherein the alkyl residue is C1 to C6, alkyls which are linear, branched or cyclic alkyls, the preferred ones being C1 to C4, and alkyls like methyl, ethyl, isopropyl, cyclopropyl and tertiary butyl, the most preferred alkyls being methyl and ethyl.
(B) Step (b) Reduction of Compounds of Formula 12 to Piperazine and its Derivatives of Formula 1:
In step (b), 3,4-dehydro-piperazine-2-one and its derivatives of formula 12 are reacted with a reducing agent to yield piperazine and its derivatives of formula 1. The reducing agents that may be used include lithium aluminum hydride (LiAlH4), sodium borohydride (NaBH4), aluminum hydride(AlH3), potassium borohydride (KBH4) or borane (B2H6) using standard conditions to produce piperazine and its derivatives of formula 1.
In step (b), preferably 1-methyl-3-phenyl-3,4-dehydro-piperazine-2-one of formula 12 (where R=CH3 and R1=Ph) is reduced with LiAlH4 to yield 1-methyl-3-phenylpiperazine of formula 1 (where R=CH3, R1=Ph and R2=H). If desired, the 1-methyl-3-phenylpiperazine of formula 1 is further converted to 1,2,3,4,10,14b-hexahydro-2-methyl-pyrazino [2,1-a]pyrido {2,3-c} [2]benzazepine of formula 17. 
This compound of formula 17 is preferably prepared by the steps comprising
(a) reacting 1-methyl-3-phenylpiperazine of formula 1 with 2-chloro-3-cyanopyridine of formula 13 to give 1-(3-cyanopyridyl-2-)-4-methyl-2-phenylpiperazine of formula 14; 
(b) hydrolyzing the compound of formula 14 to give 1-(3-carboxypyridyl-2-)-4-methyl-2-phenylpiperazine of formula 15; 
(c) reducing the compound of formula 15 to give 1-(3-hydroxymethylpyridyl-2-)-4-methyl-2-phenylpiperazine of formula 16; and 
(d) cyclizing the compound of formula 16 to give 1,2,3,4,10,14b-hexahydro-2-methyl-pyrazino[2,1-a]pyrido {2,3-c}[2]benzazepine of formula 17. 
1,2,3,4,10,14b-hexahydro-2-methyl-pyrazino[2,1-a]pyrido {2,3-c} [2]benzazepine of formula 17 is mirtazepine, a useful antidepressant. Methods of preparing mirtazepine from 1-methyl-3-phenylpiperazine are disclosed in U.S. Pat. No. 4,062,848, which is incorporated herein by reference.
Reduction of the compound of formula 15 to the compound of formula 16 (step (c)) may be effected with a metal hydride selected from lithium aluminum hydride, sodium borohydride, aluminum hydride, potassium borohydride and diborane, or by means of catalytic hydrogenation.
The step of cyclization (step (d)) may be carried out under strongly dehydrating conditions such as elevated temperature, or by addition of an acid selected from sulphuric acid, concentrated hydrochloric acid, picric acid, trifluoroacetic acid, phosphoric acid, polyphosphoric acid (PPA), phosphorous oxychloride, phosphorous trioxide, phosphorous pentoxide and Lewis acids, such as aluminum chloride, ferric chloride, zinc chloride, tin chloride, titanium chloride, boron trifluoride, antimony pentachloride or zirconium tetrachloride.
Piperazine and its derivatives of formula 1, are useful intermediates for a number of pharmaceutically active compounds, such as the antidepressant mirtazepine, the antibacterial sparfloxacin, antihistamines such as cetirizine, cinnarizine, and oxatomide, and antipsychotics such as clozapine and olanzapine.
Particularly important starting materials produced by the present invention are 1-methyl-3-phenylpiperazine for making mirtazepine, and cis 2,6-dimethylpiperazine for making sparfloxacin.
The invention is illustrated but not restricted by the description in the following examples: